Stroke And Circadian Rhythm: What's The Connection?

Circadian rhythm is the daily process where the physiological function and activity changes follow the 24-hour cycle. Many studies have shown the relationship between stroke incidence and alterations of circadian rhythm. The underlying mechanism behind stroke dependency on circadian rhythm is still unclear, apart from the fact that various chronic health conditions linked to irregular rhythms include diabetes, obesity, depression, bipolar disorder, and sleep disorders. Elevation in mean arterial blood pressure in the morning, along with changes in metabolic activity and hormone levels and a prothrombotic state with increases in plasminogen activator inhibitor 1, can stimulate the initiation of a stroke. However, other factors such as lower mean arterial pressure and heart rate at night may contribute to the onset of ischemic stroke through a hemodynamic mechanism during the sleep hours, particularly in thrombotic stroke.

Circadian Rhythm in Neuronal Susceptibility to Injury

The circadian rhythm has been shown to play a role in neuronal susceptibility to injury. This internal clock, which governs the body's circadian biological changes, can influence the vulnerability of neurons to damage. Disruptions to the circadian rhythm can increase the risk of stroke occurrence and impact neuronal injury and neurorehabilitation.

Recent data suggests that neuronal susceptibility to injury varies throughout the day, indicating a circadian variation. Experimental studies on rats with induced global cerebral ischemia revealed that the severity of cerebral damage was influenced by the time of day the ischemia occurred, with more severe effects during active hours, particularly the first hours. This finding highlights the potential impact of circadian rhythms on the extent of brain damage.

The interaction between the circadian system and brain damage is bidirectional. Post-stroke, patients often experience circadian rhythm disruption, which can be assessed through biomarkers such as melatonin and cortisol levels, core body temperature, and rest-activity patterns. This disruption can be further exacerbated by exogenous factors related to hospitalization, such as light and noise conditions, medication, and the loss of external zeitgebers of the circadian rhythm.

Managing circadian disruption in stroke patients is crucial for their recovery. Approaches to address this issue include pharmacological interventions, such as melatonin administration, and non-medication methods like bright light therapy, shifting feeding schedules, and physical activity. However, the long-term effects of these interventions on stroke recovery are not yet fully understood, and further research is needed.

Understanding the role of the circadian rhythm in neuronal susceptibility to injury has important implications for stroke prevention and treatment. By manipulating the clock mechanism and modulating neuronal susceptibility, novel astrocyte-specific targets, and pharmacological or gene therapy methods can be explored. Additionally, non-pharmacological approaches, such as regulating light and dark exposure, routine physical activity, and temporary fasting, can enhance clock function and reduce vascular risk factors associated with stroke.

Circadian Rhythm in Astrocyte Activity

Astrocytes are an important non-neuronal cell population in cerebral tissue that supports neurons and whose activity may have either neuroprotective or neurotoxic effects in case of ischemic injury. Astrocytes use blood glucose as the only source of energy for producing adenosine triphosphate (ATP), while astrocytes also employ alternative sources such as glycogen reserves, which are transformed into glucose and lactose for ATP synthesis and then delivered to neurons when needed. Astrocytes can partially support neurons by releasing ATP near synapses, where it is converted to adenosine, which reduces excitotoxicity and displays a neuroprotective effect. The data suggest that the production of ATP by astrocytes has a circadian rhythm. A circadian rhythm was also noted in the astrocyte regulation of the uptake and release of excitotoxic glutamate in cerebral tissue, with a peak in extracellular glutamate in the second half of the day in mice, when ischemia produced more neuronal damage. The same temporal pattern of fluctuation occurs in the response to oxidative stress and astrogliosis.

Desynchronization of the Endogenous Clock

• Sleep disorders and ageing
• Exogenously generated light-dark cycle
• Shift work, jet lag, and various lifestyle choices
• Stroke itself, which can directly affect the suprachiasmatic nuclei (SCN) or their connections and disturb the neuronal clock mechanism

Circadian Rhythm, Sleep Disorders and Stroke

Circadian rhythm is the 24-hour cycle of physiological processes that are part of the body's internal clock. This internal clock is responsible for the sleep-wake cycle, and its disruption may increase the risk of stroke occurrence and influence neuronal susceptibility to injury and neurorehabilitation. The peak stroke occurrence is in the morning hours, and the transition from sleep to wakefulness is an independent risk factor.

The circadian rhythm is affected by exogenous factors such as orthostatic changes, physical activity, and the sleep-awake cycle, as well as endogenous factors such as dipping patterns of blood pressure, morning prothrombotic and hypofibrinolytic states, and underlying cyclic changes in the autonomous system and humoral activity.

Sleep disturbances such as insomnia, short/long duration of sleep, and sleep-related movement disorders are risk factors for developing stroke and cardiovascular events, precipitated by circadian desynchronization.

The treatment of sleep disorders could have a protective role in stroke prevention. Melatonin, for example, can help resynchronize the internal clock, restore the natural biorhythm, and increase brain-derived neurotrophic factor (BDNF) expression.

Stroke outcome and the circadian rhythm

The time of stroke occurrence may correlate with prognosis and outcome, with worse disability scores and higher 30-day mortality for night-onset strokes.

The time of day also influences ischemic stroke outcome, with strokes that occur during the morning tending to be more severe and associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day.

Circadian rhythm and hypertension

Hypertension is a major risk factor for stroke, and the circadian rhythm is involved in the regulation of cardiovascular and cerebrovascular physiology, including heart rate and heart rate variability, sympathetic tone, blood pressure, and cerebral blood flow.

Abnormal patterns in the circadian variation of blood pressure (BP) are predictive factors for stroke, independently of awake and sleep systolic BP.

Circadian rhythm and sleep disorders

Sleep disturbances are risk factors for developing stroke and cardiovascular events, precipitated by circadian desynchronization.

Circadian rhythm and aging

Aging of the nervous tissue decreases the expression of core clock proteins, leading to the dysregulation of the endogenous clock in neurons and glia.

The circadian rhythm is a vital physiological process that influences stroke occurrence, outcome, and recovery. The treatment of sleep disorders and the resynchronization of the internal clock may improve stroke prevention and recovery.

Circadian Rhythm, Aging and Their Link to Stroke

Circadian rhythms are endogenously generated oscillations in physiology and behaviour with a near-24-hour period. The circadian system is synchronized to the 24-hour day by signals from the environment, a process called entrainment. In humans, entrainment typically occurs via light-dark exposure.

The circadian system is implicated in the regulation of processes mediating vulnerability to stroke, as well as stroke evolution and post-stroke recovery. Post-stroke circadian rhythm disruption is commonly found via the assessment of the circadian variation in the main circadian biomarkers and parameters, such as core body temperature, melatonin, and cortisol. The disruption of the diurnal sleep/wake pattern due to exogenous factors, such as hospitalization, the conditions in the intensive care unit, light conditions, and the use of sedative or hypnotic drugs can also affect circadian patterns.

The impact of these changes on post-stroke recovery and long-term prognosis is not well established and needs further investigation. However, there is increasing evidence that the circadian system is implicated in the regulation of processes mediating vulnerability to stroke. The interaction between the circadian system and brain damage is bidirectional.

Age-related changes in circadian rhythms or circadian sleep regulation may underlie the sleep timing and consolidation changes seen in aging. There are numerous reports of reduced circadian rhythm amplitude with aging. In studies of human circadian rhythms, most reports find a reduced temperature amplitude with age, and many but not all find reduced amplitude in the rhythms of melatonin and other hormones. While changes in the electrical activity of the SCN (suprachiasmatic nucleus) likely lead to alterations in output rhythm amplitude, the functional consequences are not well understood. In addition, aged animals have defects in entrainment/synchronization to light/dark cycles, which impairs their ability to predict and adapt to environmental changes.

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